Our overall goal in this program project is to understand the potential of ligands of the human immunodeficiency virus (HIV-1) gp120 envelope glycoprotein to inhibit virus entry. HIV-1 infection is initiated by entry of the virus into host cells. The entry process depends on initial attachment of virus with host, and the molecular components of this attachment process are known. HIV-1 cell recognition occurs through envelope proteins on the viral spike, a heterotrimer of the gp120/gp41 complex. The interactions between gp120 and cell receptors appear to play the central role in viral entry. Hence, the design of antagonists of gp120 interactions with cell receptors is the central objective of the Program Project. We will utilize a comprehensive, interdisciplinary, multi-group approach that will combine chemical synthesis, high-resolution structure determination, thermodynamic and kinetic binding analyses, cell infection analyses, recombinant protein production and mutagenic analyses and computational modeling. We have already demonstrated our capacity to utilize this comprehensive approach as a team, and believe our experiences so far along with current starting points arrived at in our studies will successfully lead to important advances in mechanistic understanding and productive approaches to HIV-1 entry inhibitors. The Program Project will have 5 overarching specific aims. (1) Identify novel compounds that interact with functionally important regions of the HIV-1 gp120 glycoprotein. (2) Define the binding sites of the compounds on the gp120 glycoprotein. (3) Elucidate the mechanism of inhibition of HIV-1 entry associated with the compounds. (4) Optimize gp120-binding compounds for antiviral potency. (5) Understand the impact of variation in the HIV-1 envelope glycoproteins on the antiviral efficacy of the compounds. We will accomplish these aims through 5 Projects and 2 Cores. Project 1: Structure analysis of HIV-1 entry inhibition (Hendrickson); Project 2: Peptide-inspired competitive and allosteric inhibitors of HIV-1 entry (Chaiken); Project 3: Discovery and synthesis of small molecule CD4-gp120 antagonists (Smith); Project 4: Assembly and inhibition thermodynamics (Freire); Project 5: Structure-based antagonism of HIV-1 envelope function in cell entry (Sodroski); Core A: Computational modeling (LaLonde); Core B: Protein technologies (Chaiken). This program project will examine the potential of small molecules to inhibit HIV-1 viral entry and will identify candidate inhibitors as potential antagonists for AIDS prevention and treatment. Since many viral proteins involved in disease pathogenesis exhibit the type of plasticity found for HIV-1 gp120, we believe that the approaches we develop for the gp120 system will provide experimental paradigms for prevention and treatment of other diseases as well.